Process for the preparation of protected L-alanine derivatives

ABSTRACT

The present invention is directed to a novel process for the preparation of protected L-alanine derivatives, useful as intermediates in the synthesis of compounds useful as mu/delta opioid modulators.

CROSS REFERENCE TO RELATED U.S. APPLICATION DATA

The present application is derived from and claims priority toprovisional application U.S. Ser. No. 61/108,649, filed Oct. 27, 2008,which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to a novel process for the preparationof protected L-alanine derivatives, useful as intermediates in thesynthesis of compounds useful as mu/delta opioid modulators.

BACKGROUND OF THE INVENTION

The opioid receptors were identified in the mid-1970's, and were quicklycategorized into three sub-sets of receptors (mu, delta and kappa). Morerecently the original three types of receptors have been further dividedinto sub-types. Also known is that the family of opioid receptors aremembers of the G-protein coupled receptor (GPCR) super-family. Morephysiologically pertinent are the well established facts that opioidreceptors are found throughout the central and peripheral nervous systemof many mammalian species, including humans, and that modulation of therespective receptors can elicit numerous, albeit different, biologicaleffects, both desirable and undesirable (D. S. Fries, “Analgesics”, inPrinciples of Medicinal Chemistry, 4th ed.; W. O. Foye, T. L. Lemke, andD. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp.247-269; J. V. Aldrich, “Analgesics”, Burger's Medicinal Chemistry andDrug Discovery, 5^(th) Edition, Volume 3: Therapeutic Agents, John Wiley& Sons, Inc., 1996, pp. 321-441). In the most current literature, thelikelihood of heterodimerization of the sub-classes of opioid receptorshas been reported, with respective physiological responses yetundetermined (Pierre J. M. Riviere and Jean-Louis Junien, “Opioidreceptors: Targets for new gastrointestinal drug development”, DrugDevelopment 2000, pp. 203-238).

Biological effects identified for opioid modulators have led to manyuseful medicinal agents. Most significant are the many centrally actingmu opioid agonist modulators marketed as analgesic agents to attenuatepain (e.g., morphine), as well as peripherally acting mu agonists toregulate motility (e.g., loperamide). Currently, clinical studies arecontinuing to evaluate medicinal utility of selective delta, mu, andkappa modulators, as well as compounds possessing combined sub-typemodulation. It is envisioned such explorations may lead to agents withnew utilities, or agents with minimized adverse side effects relative tocurrently available agents (examples of side effects for morphineincludes constipation, respiratory depression, and addiction potential).Some new GI areas where selective or mixed opioid modulators arecurrently being evaluated includes potential treatment for variousdiarrheic syndromes, motility disorders (post-operative ileus,constipation), and visceral pain (post operative pain, irritable bowelsyndrome, and inflammatory bowel disorders) (Pierre J. M. Riviere andJean-Louis Junien, “Opioid receptors: Targets for new gastrointestinaldrug development” Drug Development, 2000, pp. 203-238).

Around the same time the opioid receptors were identified, theenkephalins were identified as a set of endogenous opioid ligands (D. S.Fries, “Analgesics”, in Principles of Medicinal Chemistry, 4th ed.; W.O. Foye; T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins:Baltimore, Md., 1995; pp. 247-269). Schiller discovered that truncatingthe original pentapeptide enkephalins to simplified dipeptides yielded aseries of compounds that maintained opioid activity (Schiller, P. WO96/06855). However one potential drawback cited for such compounds isthe likelihood of their inherent instability (P. W. Schiller et al.,Int. J. Pept. Protein Res. 1993, 41 (3), pp. 313-316).

More recently, a series of opioid pseudopeptides containingheteroaromatic or heteroaliphatic nuclei were disclosed, however thisseries is reported showing a different functional profile than thatdescribed in the Schiller works. (L. H. Lazarus et al., Peptides 2000,21, pp. 1663-1671)

Additionally, works around morphine related structures were reported byWentland, et al, where carboxamido morphine derivatives and it's analogswere prepared (M. P. Wentland et al., Biorg. Med. Chem. Letters 2001,11, pp. 1717-1721; M. P. Wentland et al., Biorg. Med. Chem. Letters2001, 11, pp. 623-626). Wentland found that substitution for the phenolmoiety of the morphine related structures with a primary carboxamide ledanywhere from equal activities up to 40 fold reduced activities,depending on the opioid receptor and the carboxamide. It was alsorevealed that any additional N-substitutions on the carboxamidesignificantly diminished the desired binding activity.

Opioid receptor modulators, agonists or antagonists are useful in thetreatment and prevention of various mammalian disease states, forexample pain and gastrointestinal disorders, such as, diarrheicsyndromes, motility disorders, including post-operative ileus andconstipation, and visceral pain, including post-operative pain,irritable bowel syndrome, and inflammatory bowel disorders.

Breslin, H. J., et al., in U.S. Patent Publication 2005/0203143 A1,published Sep. 15, 2005, which is herein expressly incorporated byreference in its entirety, disclose opioid receptor modulators,pharmaceutical compositions including such modulators, and methods oftreatment using such modulators. The present invention is directed toprocesses for the preparation of intermediates useful in the synthesisof the opioid receptor modulators as described in U.S. PatentPublication 2005/0203143 A1.

SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation ofcompounds of formula (I)

wherein

PG¹ is a nitrogen protecting group;

R⁰ is selected from the group consisting of hydrogen, C₁₋₄alkyl andbenzyl;

R⁶ is selected from the group consisting of hydrogen and C₁₋₆alkyl;

R⁴ is aryl or heteroaryl; wherein the aryl or heteroaryl is optionallysubstituted with one to five substituents independently selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, arylC₁₋₆alkoxy,arylC₁₋₆alkylcarbonyloxy, heteroarylC₁₋₆alkylcarbonyloxy, heteroaryl,hydroxy, halogen, aminosulfonyl, formylamino, aminocarbonyl,C₁₋₆alkylaminocarbonyl, di(C₁₋₆alkyl)aminocarbonyl,heterocyclylcarbonyl, carboxy, and cyano; wherein the C₁₋₆alkyl isoptionally substituted with amino, C₁₋₆alkylamino, or (C₁₋₆alkyl)₂amino;and wherein the aryl portion of arylC₁₋₆alkylcarbonyloxy is optionallysubstituted with one to four substituents independently selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, cyano, amino andhydroxy;

and pharmaceutically acceptable enantiomers, pharmaceutically acceptablediastereomers, pharmaceutically acceptable racemates andpharmaceutically acceptable salts thereof; comprising, consisting ofand/or consisting essentially of

reacting a compound of formula (X), wherein PG¹ is a nitrogen protectinggroup, with zinc; in the presence of a source of iodine; in a firstorganic solvent or a mixture of organic solvents, wherein the firstorganic solvent is non-reactive to the source iodine; to yield thecorresponding compound of formula (XI);

reacting the compound of formula (XI) with a compound of formula (XII),wherein LG¹ is a leaving group; in the presence of a palladium catalystand phosphine ligand system; in a second organic solvent or a mixture oforganic solvents; to yield the corresponding compound of formula (I).

The present invention is further directed to a process for thepreparation of a compound of formula (I-B)

comprising, consisting of and/or consisting essentially of

reacting a compound of formula (X-B) with zinc; in the presence of asource of iodine; in a first organic solvent or mixture a mixture oforganic solvents, wherein the first organic solvent is non-reactive tothe source iodine; to yield the corresponding compound of formula(XI-B);

reacting the compound of formula (XI-B) with a compound of formula(XII-B); in the presence of a palladium catalyst and phosphine ligandsystem; in a second organic solvent or a mixture of organic solvents; toyield the corresponding compound of formula (I-B).

The present invention is further directed to a process for thepreparation of a compound of formula (II-B)

or a pharmaceutically acceptable salt thereof; comprising, consisting ofand/or consisting essentially of

reacting a compound of formula (I-B) with an oxidizing agent; in thepresence of an inorganic base; in a third organic solvent; to yield thecorresponding compound of formula (II-B).

The present invention is further directed to a product preparedaccording to any of the processes described herein. Preferably, thecompounds prepared according to the processes of the present inventionare substantially pure.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a novel process for the preparationof compounds of formula (I)

wherein PG¹, R⁰, R⁴ and R⁶ are as herein defined, and pharmaceuticallyacceptable enantiomers, diastereomers, racemates and salts thereof. Thecompounds of formula (I) are useful as intermediates in the preparationof opiod receptor modulators as disclosed in U.S. Patent PublicationUS200510203143 A1, published Sep. 15, 2005, is which is herebyincorporated by reference in its entirety.

In an embodiment, the present invention is directed to a process for thepreparation of compound of formula (I-A)

and further to a process for the preparation of a compound of formula(I-B)

also known as(S)-2-tert-butoxycarbonylamino-3-(4-cyano-2,6-dimethyl-phenyl)-propionicacid methyl ester)

The present invention is further directed to a process for thepreparation of a compound of formula (II-A)

or a pharmaceutically acceptable salt thereof; and further to a processfor the preparation of a compound of formula (II-B)

also known as(S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionicacid, or a pharmaceutically acceptable salt thereof.

In an embodiment of the present invention, PG¹ is selected from thegroup consisting of Boc and Cbz. In another embodiment of the presentinvention, PG¹ is Boc.

In an embodiment of the present invention, R⁰ is selected from the groupconsisting of C₁₋₄alkyl and benzyl. In another embodiment of the presentinvention R⁰ is selected from the group consisting of methyl, ethyl,isopropyl, t-butyl and benzyl. In another embodiment of the presentinvention, R⁰ is methyl or benzyl. In another embodiment of the presentinvention R⁰ is methyl. In another embodiment of the present invention,R⁰ is other than hydrogen.

In an embodiment of the present invention, R⁶ is selected from the groupconsisting of hydrogen and methyl. In another embodiment of the presentinvention, R⁶ is hydrogen.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of C₆₋₁₀aryl and a heteroaryl; wherein the heteroaryl isselected from the group consisting of furyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl,isoquinolinyl and quinazolinyl; and wherein the R⁴ is optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₆alkyl (wherein the C₁₋₆alkyl is optionallysubstituted with amino, C₁₋₆alkylamino, or di(C₁₋₆alkyl)amino);C₁₋₆alkoxy; phenylC₁₋₆alkoxy; phenylC₁₋₆alkylcarbonyloxy (wherein theC₁₋₆alkyl portion is optionally substituted with amino; and wherein thephenyl portion of phenylC₁₋₆alkylcarbonyloxy is optionally substitutedwith C₁₋₆alkyl, C₁₋₆alkoxy, halogen, cyano, amino, or hydroxy); a nonfused 5-membered-heteroarylC₁₋₆alkylcarbonyloxy; a non fused5-membered-heteroaryl; hydroxy; halogen; aminosulfonyl; formylamino;aminocarbonyl; C₁₋₆alkylaminocarbonyl (wherein C₁₋₆alkyl portion isoptionally substituted with amino, C₁₋₆alkylamino, or(C₁₋₆alkyl)₂amino); di(C₁₋₆alkyl)aminocarbonyl (wherein each C₁₋₆alkylportion is optionally substituted with amino, C₁₋₆alkylamino, or(C₁₋₆alkyl)₂amino); heterocyclylcarbonyl (wherein the heterocyclyl is a5-7 membered nitrogen-containing ring and wherein said heterocyclyl isattached to the carbonyl carbon via a nitrogen atom); carboxy; andcyano.

In another embodiment of the present invention, R⁴ is C₆₋₁₀aryloptionally substituted with one to three substituents independentlyselected from the group consisting of (C₁₋₃)alkyl, (C₁₋₆)alkoxy,phenyl(C₁₋₆)alkoxy; hydroxy; halogen; formylamino; aminocarbonyl;C₁₋₆alkylaminocarbonyl; (C₁₋₆alkyl)₂aminocarbonyl; heterocyclylcarbonylwherein heterocyclyl is a 5-7 membered nitrogen-containing ring and saidheterocyclyl is attached to the carbonyl carbon via a nitrogen atom;carboxy; and cyano; provided that no more than one of the substituentsis formylamino, aminocarbonyl, C₁₋₆alkylaminocarbonyl,(C₁₋₆alkyl)₂aminocarbonyl, heterocyclylcarbonyl, hydroxy, carboxy, or aphenyl-containing substituent.

In another embodiment of the present invention R⁴ is phenyl substitutedwith one to three substituents independently selected from the groupconsisting of (C₁₋₃)alkyl, (C₁₋₃)alkoxy, phenyl(C₁₋₃)alkoxy, hydroxy,C₁₋₆alkylaminocarbonyl, and aminocarbonyl; provided that no more thanone of the substituents is aminocarbonyl, C₁₋₆alkylaminocarbonyl,hydroxy, or a phenyl-containing substituent.

In another embodiment of the present invention, R⁴ is phenyl substitutedat the 4-position with hydroxy, C₁₋₃alkylaminocarbonyl, oraminocarbonyl, and further optionally substituted with one to twosubstituents independently selected from the group consisting of methyl,methoxy, and benzyloxy. In another embodiment of the present invention,R⁴ is phenyl substituted at the 4-position with hydroxy,C₁₋₃alkylaminocarbonyl, or aminocarbonyl, and further optionallysubstituted with one to two methyl substituents. In another embodimentof the present invention, R⁴ is phenyl substituted at the 4-positionwith hydroxy, C₁₋₃alkylaminocarbonyl, or aminocarbonyl, and furthersubstituted at the 2- and 6-positions with methyl substituents.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I), wherein the stereo-center asindicated by the “*” is present in an enantiomeric excess of the (R)enantiomer. In another embodiment, the present invention s directed to aprocess for the preparation of a compound of formula (I), wherein thestereo-center as indicated by the “*” is present in an enantiomericexcess of the (S) enantiomer.

As used herein, unless otherwise noted, the term “alkyl” whether usedalone or as part of a substituent group refers to straight and branchedcarbon chains having 1 to 8 carbon atoms or any number of carbon atomswithin the end points of this range. The term “alkoxy” refers to an—Oalkyl substituent group, wherein alkyl is as defined supra. An alkyland alkoxy chain may be substituted on a single carbon atom. Insubstituent groups with multiple alkyl groups such asdi(C₁₋₆alkyl)amino- the C₁₋₆alkyl groups of the dialkylamino may be thesame or different.

The term “heterocyclyl” refers to a nonaromatic cyclic ring of 5 to 7members in which 1 to 2 members are nitrogen, or a nonaromatic cyclicring of 5 to 7 members in which zero, one or two members are nitrogenand up to two members are oxygen or sulfur; wherein, optionally, thering contains zero to one unsaturated bonds, and, optionally, when thering is of 6 or 7 members, it contains up to two unsaturated bonds. Theterm “heterocyclyl” includes a 5 to 7 membered monocyclic heterocyclicring fused to a benzene ring (benzo fused heterocyclyl), a 5 or 6membered heteroaryl ring (containing one of O, S or N and, optionally,one additional nitrogen), a 5 to 7 membered cycloalkyl or cycloalkenylring, a 5 to 7 membered heterocyclyl ring (of the same definition asabove but absent the option of a further fused ring) or fused with thecarbon of attachment of a cycloalkyl, cycloalkenyl or heterocyclyl ringto form a spiro moiety. For compounds of the instant invention, thecarbon atom ring members that form the heterocyclyl ring are fullysaturated. Other compounds of the invention may have a partiallysaturated heterocyclyl ring. The term “heterocyclyl” also includes a 5to 7 membered monocyclic heterocycle bridged to form bicyclic rings.Such compounds are not considered to be fully aromatic and are notreferred to as heteroaryl compounds. Examples of heterocyclyl groupsinclude, and are not limited to, pyrrolinyl (including 2H-pyrrole,2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl,imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, and piperazinyl.

The term “aryl” refers to an unsaturated, aromatic monocyclic ring of 6carbon members or to an unsaturated, aromatic polycyclic ring of from 10to 14 carbon members. Examples of such aryl rings include phenyl,naphthalenyl, or anthracenyl. Preferred aryl groups for the practice ofthis invention are phenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic ring of 5 or 6 memberswherein the ring consists of carbon atoms and has at least oneheteroatom member. Suitable heteroatoms include N, O, or S. In the caseof 5 membered rings, the heteroaryl ring contains one member of N, O, orS and, in addition, may contain up to three additional nitrogens. In thecase of 6 membered rings, the heteroaryl ring may contain from one tothree nitrogen atoms. For the case wherein the 6 membered ring has threenitrogens, at most two nitrogen atoms are adjacent. Optionally, theheteroaryl ring is fused to a benzene ring (benzo fused heteroaryl), a 5or 6 membered heteroaryl ring (containing one of O, S, or N and,optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl ringor a 5 to 7 membered heterocyclo ring (as defined supra but absent theoption of a further fused ring). Examples of heteroaryl groups include,and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl; fusedheteroaryl groups include indolyl, isoindolyl, indolinyl, benzofuryl,benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolizinyl,quinolinyl, isoquinolinyl and quinazolinyl.

The term “arylalkyl” means an alkyl group substituted with an aryl group(e.g., benzyl and phenethyl). Similarly, the term “arylalkoxy” indicatesan alkoxy group substituted with an aryl group (e.g., benzyloxy).

The term “halogen” refers to fluorine, chlorine, bromine and iodine.Substituents that are substituted with multiple halogens are substitutedin a manner that provides compounds that are stable.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., arylalkyl, alkylamino) it is tobe interpreted as including those limitations given above for “alkyl”and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆) refersindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger substituent in which alkyl appears as itsprefix root. For alkyl, and alkoxy substituents the designated number ofcarbon atoms includes all of the independent member included in therange specified individually and all the combination of ranges within inthe range specified. For example C₁₋₆alkyl would include methyl, ethyl,propyl, butyl, pentyl and hexyl individually, as well as,sub-combinations thereof (e.g., C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₂₋₆, C₃₋₆,C₄₋₆, C₅₋₆, C₂₋₅, etc.).

When a particular group is “substituted” (e.g., alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, etc.), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

As used herein, the notation “*” shall denote the presence of astereogenic center. Where the compounds according to this invention haveat least one chiral center, they may accordingly exist as enantiomers.Where the compounds possess two or more chiral centers, they mayadditionally exist as diastereomers. It is to be understood that allsuch isomers and mixtures thereof are encompassed within the scope ofthe present invention. Preferably, wherein the compound is present as anenantiomer, the enantiomer is present at an enantiomeric excess ofgreater than or equal to about 80%, more preferably, at an enantiomericexcess of greater than or equal to about 90%, more preferably still, atan enantiomeric excess of greater than or equal to about 95%, morepreferably still, at an enantiomeric excess of greater than or equal toabout 98%, most preferably, at an enantiomeric excess of greater than orequal to about 99%. Similarly, wherein the compound is present as adiastereomer, the diastereomer is present at an diastereomeric excess ofgreater than or equal to about 80%, more preferably, at andiastereomeric excess of greater than or equal to about 90%, morepreferably still, at an diastereomeric excess of greater than or equalto about 95%, more preferably still, at an diastereomeric excess ofgreater than or equal to about 98%, most preferably, at andiastereomeric excess of greater than or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

AcCN = Acetonitrile Boc, or BOC = tert-Butoxycarbonyl Cbz =Benzyloxycarbonyl DMA or DMAc = Dimethylacetamide DMF =N,N-Dimethylformamide DMSO = Dimethylsulfoxide EtOAc = Ethyl acetateHPLC = High Pressure Liquid Chromatography MeOH = Methanol 2-Me-THF =2-methyl-tetrahydrofuran NMP = N-Methyl-pyrrolidone Pd₂(dba)₃ =Tris(dibenzylidene acetone)dipalladium(0) Pd(PPh₃)₄ =Tetrakistriphenylphosphine palladium (0) Pd(PPh₃)₂Cl₂ =Bis(triphenylphosphine)palladium (II) chloride P(o-tol)₃ = Tri-(o-tolyl)phosphine PPh₃ = Triphenyl phosphine THF = Tetrahydrofuran

As used herein, unless otherwise noted, the term “substantially purecompound” shall mean that the mole percent of impurities in the isolatedcompound is less than about 5 mole percent, preferably less than about 2mole percent, more preferably, less than about 0.5 mole percent, mostpreferably, less than about 0.1 mole percent. In an embodiment of thepresent invention, the compound of formula (I) is prepared as asubstantially pure compound. In an embodiment of the present invention,the compound of formula (I-A) is prepared as a substantially purecompound. In another embodiment of the present invention, the compoundof formula (I-B) is prepared as a substantially pure compound. In anembodiment of the present invention, the compound of formula (II-A) isprepared as a substantially pure compound. In another embodiment of thepresent invention, the compound of formula (II-B) is prepared as asubstantially pure compound.

As used herein, unless otherwise noted, the term “substantially free ofa corresponding salt form(s)” when used to described the compound offormula (I) shall mean that mole percent of the corresponding saltform(s) in the isolated base of formula (I) is less than about 5 molepercent, preferably less than about 2 mole percent, more preferably,less than about 0.5 mole percent, most preferably less than about 0.1mole percent. In an embodiment of the present invention, the compound offormula (I) is prepared in a form which is substantially free ofcorresponding salt form(s). In an embodiment of the present invention,the compound of formula (II-A) is prepared in a form that issubstantially free of corresponding salt form(s). In another embodimentof the present invention, the compound of formula (II-B) is prepared ina form that is substantially free of corresponding salt form(s).

As more extensively provided in this written description, terms such as“reacting” and “reacted” are used herein in reference to a chemicalentity that is any one of: (a) the actually recited form of suchchemical entity, and (b) any of the forms of such chemical entity in themedium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product. One skilledin the art will further recognize that, in the specification and claimsas presented herein, wherein a reagent or reagent class/type (e.g.,base, solvent, etc.) is recited in more than one step of a process, theindividual reagents are independently selected for each reaction stepand may be the same of different from each other. For example, where twosteps of a process recite an organic or inorganic base as a reagent, theorganic or inorganic base selected for the first step may be the same ordifferent than the organic or inorganic base of the second step.Further, one skilled in the art will recognize that wherein a reactionstep of the present invention may be carried out in a variety ofsolvents or solvent systems, said reaction step may also be carried outin a mixture of the suitable solvents or solvent systems. One skilled inthe art will further recognize that wherein two consecutive reaction orprocess steps are run without isolation of the intermediate product(i.e., the product of the first of the two consecutive reaction orprocess steps), then the first and second reaction or process steps maybe run in the same solvent or solvent system; or, alternatively, may berun in different solvents or solvent systems following solvent exchange,which may be completed according to known methods.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any rangetherein.

Examples of suitable solvents, bases, reaction temperatures, and otherreaction parameters and components are provided in the detaileddescriptions which follows herein. One skilled in the art will recognizethat the listing of said examples is not intended, and should not beconstrued, as limiting in any way the invention set forth in the claimswhich follow thereafter.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to Cl, Br, I, mesylate, tosylate, and the like.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” refers to a group that may be attached to a nitrogen atom toprotect the nitrogen atom from participating in a reaction and that maybe readily removed following the reaction. Suitable nitrogen protectinggroups include carbamates—groups of the formula —C(O)O—R wherein R is,for example, methyl, ethyl, t-butyl, benzyl, phenylethyl, CH₂═CH—CH₂—,and the like; amides—groups of the formula —C(O)—R′ wherein R′ is forexample methyl, phenyl, trifluoromethyl, and the like; N-sulfonylderivatives—groups of the formula —SO₂—R″ wherein R″ is for exampletolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

One skilled in the art will recognize that where a reaction step of thepresent invention may be carried out in a variety of solvents or solventsystems, said reaction step may also be carried out in a mixture of thesuitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as, theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as, (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Additionally, chiral HPLC against a standard may be used to determinepercent enantiomeric excess (% ee). The enantiomeric excess may becalculated as follows[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%

where Rmoles and Smoles are the R and S mole fractions in the mixturesuch that Rmoles+Smoles=1. The enantiomeric excess may alternatively becalculated from the specific rotations of the desired enantiomer and theprepared mixture as follows:ee=([α−obs]/[α−max])×100.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts that may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid, such as,hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid and phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium and potassiumsalts; alkaline earth metal salts, e.g., calcium and magnesium salts;and salts formed with suitable organic ligands, e.g., quaternaryammonium salts. Thus, representative pharmaceutically acceptable saltsinclude acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate.

Representative acids that may be used in the preparation ofpharmaceutically acceptable salts include: acids including acetic acid,2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid, and undecylenic acid.

Representative bases that may be used in the preparation ofpharmaceutically acceptable salts include: bases including, ammonia,L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol,diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine,ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole,L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine,piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine,secondary amine, sodium hydroxide, triethanolamine, tromethamine, andzinc hydroxide.

The present invention is directed to a process for the preparation ofcompounds of formula (I) as described in more detail in Scheme 1 below.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, wherein PG¹ is asuitably selected nitrogen protecting group such as Boc, Cbz, and thelike, preferably Boc; is reacted with zinc, preferably zinc powder;wherein the zinc is preferably present in an amount in the range of fromabout 0.5 to about 3.0 molar equivalents, more preferably present in anamount in the range of from about 0.5 to about 1.5 molar equivalents,more preferably about 1.1 molar equivalents; in the presence of a sourceof iodine, preferably iodine; wherein the source of iodine is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably in an amount in the range of from about 0.1to about 0.5 molar equivalents, more preferably about 0.3 molarequivalents, more preferably in a catalytic amount sufficient toactivate the zinc; in a first organic solvent or mixture thereof,wherein the first organic solvent is non-reactive to the source iodine,such as, DMAc, a mixture of DMAc and 2-methyl-THF, THF, toluene, DMF,and the like, more preferably DMAc; preferably at a temperature in therange of from about −20° C. to about 10° C., more preferably at atemperature of less than about 10° C., more preferably at about −8° C.;to yield the corresponding compound of formula (XI). Preferably, thecompound of formula (XI) is not isolated. Preferably, the zinc andsource of iodine are mixed prior to addition to the compound of formula(X), to activate the zinc.

The compound of formula (XI) is reacted with a suitably substitutedcompound of formula (XII), wherein LG¹ is a suitably selected leavinggroup such as, Cl, Br, I, and the like, preferably Br; wherein thecompound of formula (XII) is preferably present in an amount in therange of from about 0.1 to about 3.0 molar equivalents, more preferablyin an amount in the range of from about 0.25 to about 1.0 molarequivalents, more preferably in an amount in the range of from about 0.5to about 1.1 molar equivalents; in the presence of a palladium catalystand phosphine ligand system such as Pd₂(dba)₃ in combination withP(o-tol)₃, palladium chloride in combination with PPh₃, Pd(PPh₃)₂Cl₂,Pd(PPh₃)₄, and the like, more preferably Pd₂(dba)₃ in combination withP(o-tol)₃, wherein the palladium catalyst and phosphine ligand system ispreferably present in a catalytic amount; in a second organic solvent ormixture thereof such as, DMAc, a mixture of DMAc and 2-methyl-THF, THF,DMF, toluene, and the like, more preferably DMAc; preferably in the samesolvent as used in the previous step; preferably at a temperature in therange of from about 50° C. to about 100° C., more preferably at about80° C.; to yield the corresponding compound of formula (I). Preferably,the compound of formula (XI) is added to a mixture of the compound offormula (XII), the palladium catalyst and the phosphine agent.

The present invention is further directed to a process for thepreparation of a compound of formula (I-A) as described in more detailin Scheme 2, below.

Accordingly, a suitably substituted compound of formula (X-A), a knowncompound or compound prepared by known methods, wherein PG¹ is asuitably selected nitrogen protecting group such as Boc, Cbz, and thelike, preferably Boc; is reacted with zinc, preferably zinc powder;wherein the zinc is preferably present in an amount in the range of fromabout 0.5 to about 3.0 molar equivalents, more preferably present in anamount in the range of from about 0.5 to about 1.5 molar equivalents,more preferably about 1.1 molar equivalents; in the presence of a sourceof iodine, preferably iodine; wherein the source of iodine is preferablypresent in an amount in the range of from about 0.1 to about 1.0 molarequivalents, more preferably in an amount in the range of from about 0.1to about 0.5 molar equivalents, more preferably about 0.3 molarequivalents, more preferably in a catalytic amount sufficient toactivate the zinc; in a first organic solvent or mixture thereof,wherein the first organic solvent is non-reactive to the source iodine,such as, DMAc, a mixture of DMAc and 2-methyl-THF, THF, toluene, DMF,and the like, more preferably DMAc; preferably at a temperature in therange of from about −20° C. to about 10° C., more preferably at atemperature of less than about 10° C., more preferably at about −8° C.;to yield the corresponding compound of formula (XI-A). Preferably, thecompound of formula (XI-A) is not isolated. Preferably, the zinc andsource of iodine are mixed prior to addition to the compound of formula(V-A), to activate the zinc.

The compound of formula (XI-A) is reacted with a suitably substitutedcompound of formula (XII-A), wherein LG¹ is a suitably selected leavinggroup, such as, Cl, Br, I, and the like, preferably Br; wherein thecompound of formula (XII-A) is preferably present in an amount in therange of from about 0.1 to about 3.0 molar equivalents, more preferablyin an amount in the range of from about 0.25 to about 1.0 molarequivalents, more preferably in an amount in the range of from about 0.5to about 1.1 molar equivalents; in the presence of a palladium catalystand phosphine ligand system such as Pd₂(dba)₃ in combination withP(o-tol)₃, palladium chloride in combination with PPh₃, Pd(PPh₃)₂Cl₂,Pd(PPh₃)₄, and the like, more preferably Pd₂(dba)₃ in combination withP(o-tol)₃, wherein the palladium catalyst and phosphine ligand system ispreferably present in a catalytic amount; in a second organic solvent ormixture thereof, such as, DMAc, a mixture of DMAc and 2-methyl-THF, THF,DMF, toluene, and the like, more preferably DMAc; preferably in the samesolvent as used in the previous step; preferably at a temperature in therange of from about 50° C. to about 100° C., more preferably at about80° C.; to yield the corresponding compound of formula (I-A).Preferably, the compound of formula (XI-A) is added to a mixture of thecompound of formula (XII-A), the palladium catalyst and the phosphineagent.

The present invention is further directed to a process for thepreparation of a compound of formula (I-B), as described in more detailin Scheme 3,

Accordingly, a suitably substituted compound of formula (X-B), a knowncompound or compound prepared by known methods, is reacted with zinc,preferably zinc powder; wherein the zinc is preferably present in anamount in the range of from about 0.5 to about 3.0 molar equivalents,more preferably present in an amount in the range of from about 0.5 toabout 1.5 molar equivalents, more preferably about 1.1 molarequivalents; in the presence of a source of iodine, preferably iodine;wherein the source of iodine is preferably present in an amount in therange of from about 0.1 to about 1.0 molar equivalents, more preferablyin an amount in the range of from about 0.1 to about 0.5 molarequivalents, more preferably about 0.3 molar equivalents, morepreferably in a catalytic amount sufficient to activate the zinc; in afirst organic solvent or mixture thereof, wherein the first organicsolvent is non-reactive to the source iodine, such as, DMAc, a mixtureof DMAc and 2-methyl-THF, THF, toluene, DMF, and the like, morepreferably DMAc; preferably at a temperature in the range of from about−20° C. to about 10° C., more preferably at a temperature of less thanabout 10° C., more preferably at about −8° C.; to yield thecorresponding compound of formula (XI-B). Preferably, the compound offormula (XI-B) is not isolated. Preferably, the zinc and source ofiodine are mixed prior to addition to the compound of formula (V-B), toactivate the zinc.

The compound of formula (XI-B) is reacted with a suitably substitutedcompound of formula (XII-B), wherein the compound of formula (XII-B) ispreferably present in an amount in the range of from about 0.1 to about3.0 molar equivalents, more preferably in an amount in the range of fromabout 0.25 to about 1.0 molar equivalents, more preferably in an amountin the range of from about 0.5 to about 1.1 molar equivalents; in thepresence of a palladium catalyst and phosphine ligand system such asPd₂(dba)₃ in combination with P(o-tol)₃, palladium chloride incombination with PPh₃, Pd(PPh₃)₂Cl₂, Pd(PPh₃)₄, and the like, morepreferably Pd₂(dba)₃ in combination with P(o-tol)₃, wherein thepalladium catalyst and phosphine ligand system is preferably present ina catalytic amount; in a second organic solvent or mixture thereof, suchas, DMAc, a mixture of DMAc and 2-methyl-THF, THF, DMF, toluene, and thelike, more preferably DMAc; preferably in the same solvent as used inthe previous step; preferably at a temperature in the range of fromabout 50° C. to about 100° C., more preferably at about 80° C.; to yieldthe corresponding compound of formula (I-B). Preferably, the compound offormula (XI-B) is added to a mixture of the compound of formula (XII-B),the palladium catalyst and the phosphine agent.

The present invention is further directed to a process for thepreparation of a compound of formula (II-A), as described in more detailin Scheme 4, below.

Accordingly, a suitably substituted compound of formula (I-A), whereinR⁰ is preferably other than hydrogen, and wherein PG¹ is a suitablyselected nitrogen protecting group such as Boc, Cbz, and the like,preferably PG¹ is Boc, is reacted with a suitably selected oxidizingagent, such as, hydrogen peroxide, LiOH, LiOOH, and the like, preferably30% hydrogen peroxide; wherein the oxidizing agent is preferably presentin an excess amount; in the presence of an inorganic base, such as,potassium carbonate, sodium carbonate, sodium percarbonate, and thelike, preferably potassium carbonate; wherein the inorganic base ispreferably present in an amount in the range of from about 1.0 to about3.0 molar equivalent, more preferably in an amount of about 1.6 molarequivalents; in a third organic solvent, such as, DMSO, DMF, DMAc, NMP,and the like, preferably DMSO; at a temperature in the range of fromabout room temperature to about 60° C., preferably at about 45° C.; toyield the corresponding compound of formula (II-A).

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (II-B), as described in more detailin Scheme 5, below.

Accordingly, a suitably substituted compound of formula (I-B), isreacted with a suitably selected oxidizing agent, such as, hydrogenperoxide, LiOH, LiOOH, and the like, preferably about 30% hydrogenperoxide; wherein the oxidizing agent is preferably present in an excessamount, more preferably wherein the oxidizing agent is an excess amountof about 30% hydrogen peroxide; in the presence of an inorganic base,such as, potassium carbonate, sodium carbonate, sodium percarbonate, andthe like, preferably potassium carbonate; wherein the inorganic base ispreferably present in an amount in the range of from about 1.0 to about3.0 molar equivalent, more preferably in an amount of about 1.6 molarequivalents; in a third organic solvent such as DMSO, DMF, DMAc, NMP,and the like, preferably DMSO; at a temperature in the range of fromabout room temperature to about 60° C., preferably at about 45° C.; toyield the corresponding compound of formula (II-B).

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1 Preparation of2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionicacid methyl ester

STEP A

Dry DMAc (300 mL), 2-Me-THF (150 mL), I₂ (25.4 g, 0.10 mol) and zincpowder (294.3 g, 4.5 mol), were added under nitrogen to a 3 Lfour-necked round bottom flask equipped with an addition funnel,mechanical stirrer, heating mantel, condenser and thermocouple. Theresulting slurry was stirred until the red color of I₂ disappeared(about 2 minutes). During the addition, a temperature increase wasobserved (from 23° C. to 43° C.). The resulting mixture was cooled downusing an ice/NaCl bath to about −5° C. to −2° C. While at thistemperature, a solution of Boc-6-iodo-alanine-OCH₃ (also known as2-tert-butoxycarbonylamino-3-iodo-propionic acid methyl ester, 658.3 g,2.0 mol) in a mixture of DMAc (250 mL) and 2-Me-THF (500 mL) was addedslowly over a period of 2 hours. The temperature of the resultingmixture was maintained below 10° C. and the mixture aged for a period ofabout 1-2 hours in the ice bath, then warmed to about 15° C. to yield amixture. The resulting cooled mixture was used in the next step withoutfurther manipulation.

STEP B

4-Iodo-3,5-dimethyl-benzamide (275 g, 1.0 mol), 2-Me-THF (500 mL) andDMA (200 mL), were added to a 5 L four-necked round bottom flaskequipped with mechanical stirrer, heating mantel, condenser,thermocouple and nitrogen inlet. P(o-tol)₃ (24.5 g, 0.08 mol) andPd₂(dba)₃ (36.6 g, 0.04 mol) were added to the suspension and theresulting slurry was heated to 45-50° C. While at this temperature, themixture prepared in STEP A was added by cannula over a period of about1.5-2 hours. The resulting mixture was cooled to ambient temperature.Silica (275 g) was added and the slurry stirred for about 30 minutes.The silica pad was washed with 2-Me-THF (3×500 mL) and EtOAc (3×1 L).The resulting solution was quenched with 2 L of 1.0N aqueous HCl and thelayers were separated. The acidic layer was back extracted with EtOAc(2×1 L). The organic layer was concentrated to about 5.0 L in arotoevaporator and rinsed with water (3×1 L), and with 50% brine (2.0L). The solvents were removed by rotoevaporator to yield an off-whitesolid.

The title compound was crystallized from EtOAc (2 L) and heptane (2 L)as follows. After 16 hours the resulting mixture was cooled in an icebath for 2 hours and more heptane (500 mL) was added to complete theprecipitation. The solid was filtered and dried in a vacuum oven at 55°C. for 48 hours to yield the title compound as a white solid.

Example 2 Preparation of(S)-2-tert-Butoxycarbonylamino-3-(4-cyano-2,6-dimethyl-phenyl)-propionicacid methyl ester

A 50 mL three-necked round bottom flask equipped with an additionfunnel, magnetic stirrer, heating mantel, and thermocouple was chargedunder nitrogen dry DMAc (2 mL), I₂ (38.1 mg, 0.15 mmol) and zinc powderactivated (washed with 10% HCl, rinsed with H₂O and acetone) (393 mg, 6mmol). The resulting mixture was stirred at 23° C. until the red colorof I₂ disappeared (2 minutes). A solution of Boc-β-iodo-L-alanine methylester (1 g, 3 mmol) in DMAc (2 mL) was added slowly, (temperature changefrom 21° C. to 29° C.) and the resulting mixture was stirred at 80° C.for 0.5-1 hour, then co cooled to 35° C. To the resulting mixture wereadded, successively, 4-bromo-3,5-dimethyl-benzonitrile (315 mg, 1.5mmol) in DMAc (6 mL), P(o-tol)₃ (36.5 mg, 0.12 mmol) and Pd₂(dba)₃ (55mg, 0.06 mmol). The resulting mixture was heated to 70° C., withstirring for 1 hour, then cooled to ambient temperature. The resultingmixture was diluted with EtOAc (15 mL) and filtered with STAND SUPER-CEL815520. The EtOAc solution was quenched with 1 N HCl (40 mL) andextracted with ethyl acetate (20 mL). The combined organic phases werewashed with H₂O (2×50 mL) and then with 50% brine, dried over Na₂SO₄,filtered and evaporated to dryness in vacuo to yield a brown solid. Thetitle compound was crystallized from EtOAc (5 mL) and heptane (40 mL) toyield a white solid.

Example 3 Preparation of(S)-2-tert-Butoxycarbonylamino-3-(4-cyano-2,6-dimethyl-phenyl)-propionicacid methyl ester

STEP A: Boc-β-iodo-Alanine methyl ester

A 2 L four-necked round-bottomed flask equipped with a nitrogen inlet, amechanical stirrer, an addition funnel and a thermocouple was chargedwith anhydrous DMAc (500 mL) and iodine (16.8 g, 0.06 mol) to yield ared solution. To the stirred solution was then added zinc powder (143.9g, 2.2 mol). The red color of the resulting mixture was observed todisappear in about 2 minutes, and an exotherm (22° C. to about 36° C.)was observed. The resulting mixture was cooled to −8° C. and then asolution of N-(tert-butoxycarbonyl)-3-iodo-L-alanine methyl ester (658g, 2.0 mol) in anhydrous DMAc (500 mL) was added slowly over about 2hours, maintaining the mixture temperature at below about 10° C.,without stirring. The resulting cooled mixture was used in the next stepwithout further manipulation.

STEP B:(S)-2-tert-Butoxycarbonylamino-3-(4-cyano-2,6-dimethyl-phenyl)-propionicacid methyl ester

A 5 L three-necked round-bottomed flask equipped with a nitrogen inlet,a mechanical stirred, an addition funnel and a thermocouple was chargedwith 4-bromo-3,5-dimethyl-benzonitrile (210 g, 1.0 mol) and DMAc (750ml). The resulting suspension was stirred and heated to 35° C. todissolve the solids. To the resulting mixture was then added P(o-tol)₃(6.0 g, 0.02 mol), Pd₂(dba)₃ (9.2 g, 0.01 mol) and the resulting mixtureheated to about 75-80° C. The cooled mixture prepared in STEP A abovewas added by cannula to the reaction mixture at a rate which maintainedthe temperature at about 75-80° C. (about 2 hours). The resultingsuspension was cooled to ambient temperature, then aged overnight withmoderate agitation. The resulting suspension was then heated to about35-40° C., filtered with silica (540 g). The silica bed was washed withDMAc (400 mL×2), the combined DMAc solutions cooled to about 0-5° C. andthen added slowly to a mixture of ice and deionized water. The resultingmixture was maintained cold for 2 hours, over which time a white solidwas observed to precipitate. The resulting mixture was then warmed toambient temperature and aged overnight. The solid precipitate was cooledby vacuum filtration using a Buchner funnel. The filter cake was rinsedwith deionized water (1 L×3), air dried overnight, then dried in avacuum oven overnight. MeOH (1 L) was added to the solid and theresulting slurry was cooled to about 0-5° C., then aged at thistemperature for 1 hour, with stirring. The solid was collected byfiltration, washed with cold methanol (400 mL) and dried in a vacuumoven at 45° C. to yield the title compound as an off-white solid.

Example 4 Preparation of 4-Bromo-3,5-dimethyl-benzonitrile

4-Bromo-3,5-dimethylphenol (50.0 g, 0.25 mol from Aldrich 99%) andpyridine (250 mL), were added to a 3 necked, 2.0 L round bottomed flaskequipped with addition funnel, mechanical stirrer and thermocouple. Theresulting solution was cooled to 0° C. and trifluoromethanesulfonicanhydride (triflic anhydride) (80.5 g, 0.285 mol from Aldrich 99%) wasadded dropwise over a period of 2 hours. After the addition, theresulting mixture was maintained at 0° C. for 15 minutes, then leftovernight at room temperature. After 16 hours the resulting mixture wascooled down in an ice bath and quenched with H₂O (1.7 L), and EtOAc (1.7L). The layers of the resulting biphasic mixture were separated and theorganic layer was treated with HCl 2N (2×1.0 L), then rinsed once withwater (1.0 L) and once with 50% brine. The organic layer was dried overNa₂SO₄, then concentrated to dryness by rotavapor to yieldtrifluoromethanesulfonic acid 4-bromo-3,5-dimethyl-phenyl ester as thickoil.

Trifluoro-methanesulfonic acid 4-bromo-3,5-dimethyl-phenyl ester (79.8g, 0.24 mol) and AcCN (500 mL) were added to a 3 necked, 2.0 L roundbottom flask equipped with mechanical stirrer, nitrogen inlet adapter,heating mantle and thermocouple. To the resulting solution were thenadded Pd(PPh₃)₄ (27.7 g, 0.024 mol), CuI (9.2 g, 0.048 mol) and Zn(CN)₂(79.8 g, 0.24 mol). The resulting mixture was stirred for 45 minutes at50° C., DMAc (150 mL) was added and the temperature was increased to80-88° C. and the mixture aged at this temperature overnight. Theresulting mixture was cooled to ambient temperature, diluted with EtOAc(200 mL), and filtered with STAND SUPER-CEL 815520. The SUPER-CEL cakewas rinsed with EtOAc (200 mL×6). The EtOAc solutions were combined andquenched with a 4:1:4 mixture of saturated NH₄Cl: concentrated NH₄OH:H₂O(240 mL:60 mL:240 mL). The layers were separated and the organic layerwas rinsed once with water (500 mL) and once with brine (500 mL), thenconcentrated to dryness in vacuo to yield a red thick oil. The titlecompound was crystallized from EtOAc (135 mL) and heptane (500 mL) toyield white-yellowish crystal.

Example 5 Preparation of(S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionicacid

A 50 mL three-necked round bottom flask equipped with magnetic stirrer,and thermocouple was charged under nitrogen with(S)-2-tert-butoxycarbonylamino-3-(4-cyano-2,6-dimethyl-phenyl)-propionicacid methyl ester (166.2 mg, 0.5 mmol), DMSO (5.0 mL), and K₂CO₃ (75 mg,0.5 mmol) and the resulting mixture cooled in an ice bath. To theresulting mixture was then added 30% H₂O₂ (110 μl), dropwise via asyringe. The resulting mixture was then allowed to warm up to ambienttemperature, with the solids observed to dissolve to yield a clearsolution. After stirring for about 2 hours at 45-50° C., water (10 mL)was added, cooling was applied, and a precipitated product isolated byfiltration. The isolated white solid was washed with water (2×25 mL),then dried for 24 hours on high vacuum pump to yield the title compoundas a white solid.

Example 6 Preparation of2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionicacid

2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionicacid methyl ester (250 g, 0.713 mol), DMSO (750 mL) and 30% H₂O₂ (250mL), were added to a 5 L three-necked round bottom flask equipped withaddition funnel, mechanical stirrer, heating mantel, reflux condenser,thermocouple and nitrogen inlet. Potassium carbonate (158 g, 1.14 mol,1.6 eq) was dissolved in water (750 mL) and added dropwise over 30minutes. During the addition, a temperature increase was observed (from23° C. to 34° C.). The resulting mixture was warmed up to about 42-45°C. and the progress of the reaction monitored by HPLC. After 3 hours, tothe warm mixture was added activated carbon (ECOSORB-941) (37.5 g, 15%by weight). The resulting slurry was refluxed for 1 hour, and thenfiltered hot through CELITE®. The CELITE® pad was rinsed with H₂O (1.5L). The resulting mixture was cooled to about 10° C. and quenched with2.0N HCl (pH 2, 1.22 L), to yield a mixture comprising a white solidprecipitated. The mixture was aged under agitation for a period of about4 hours in an ice bath and then filtered and dried for 48 hours in avacuum oven to yield the title compound as a white crystalline solid.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

We claim:
 1. A process for the preparation of a compound of formula (I)

wherein PG¹ is a nitrogen protecting group; R⁰ is selected from thegroup consisting of hydrogen, C₁₋₄-alkyl and benzyl; R⁶ is selected fromthe group consisting of hydrogen and C₁₋₆alkyl; R⁴ is aryl orheteroaryl; wherein the aryl or heteroaryl is optionally substitutedwith one to five substituents independently selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxy, arylC₁₋₆alkoxy,arylC₁₋₆alkylcarbonyloxy, heteroarylC₁₋₆alkylcarbonyloxy, heteroaryl,hydroxy, halogen, aminosulfonyl, formylamino, aminocarbonyl,C₁₋₆alkylaminocarbonyl, di(C₁₋₆alkyl)aminocarbonyl,heterocyclylcarbonyl, carboxy, and cyano; wherein the C₁₋₆alkyl isoptionally substituted with amino, C₁₋₆alkylamino, or (C₁₋₆alkyl)₂amino;and wherein the aryl portion of arylC₁₋₆alkylcarbonyloxy is optionallysubstituted with one to four substituents independently selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, cyano, amino andhydroxy; and pharmaceutically acceptable enantiomers, pharmaceuticallyacceptable diastereomers, pharmaceutically acceptable racemates andpharmaceutically acceptable salt thereof; comprising

reacting a compound of formula (X), wherein PG¹ is a nitrogen protectinggroup, with zinc; in the presence of a source of iodine; in a firstorganic solvent, or a mixture of organic solvents wherein the firstorganic solvent is non-reactive to the source iodine; to yield thecorresponding compound of formula (XI);

reacting the compound of formula (XI) with a compound of formula (XII),wherein LG¹ is a leaving group; in the presence of a palladium catalystand phosphine ligand system; in a second organic solvent or a mixture oforganic solvents; to yield the corresponding compound of formula (I). 2.The process as in claim 1 wherein PG¹ is Boc.
 3. The process as in claim1, wherein R⁰ is methyl.
 4. The process as in claim 1, wherein the zincis zinc powder.
 5. The process as in claim 4, wherein the zinc powder ispresent in an amount in the range of from about 0.5 to about 1.5 molarequivalents.
 6. The process as in claim 1, wherein the source of iodineis iodine.
 7. The process as in claim 6, wherein the iodine is presentin an amount in the range of from about 0.1 to about 0.5 molarequivalents.
 8. The process as in claim 1, wherein the first organicsolvent is DMAc.
 9. The process as in claim 1, wherein the compound offormula (X) is reacted with the zinc at a temperature of less than about10° C.
 10. The process as in claim 1, wherein the zinc and source ofiodine are mixed prior to addition to the compound of formula (X). 11.The process as in claim 1, wherein LG¹ is bromo.
 12. The process as inclaim 1, wherein the compound of formula (XII) is present in an amountin the range of from about 0.25 to about 1.0 molar equivalents.
 13. Theprocess as in claim 1, wherein the palladium catalyst and phosphineligand system is a combination of Pd₂(dba)₃ and P(o-tol)₃.
 14. Theprocess as in claim 1, wherein the second organic solvent is DMAc. 15.The process as in claim 1, wherein the compound of formula (X) isreacted with the compound of formula (XII) at a temperature in the rangeof from about 50° C. to about 100° C.
 16. The process as in claim 1,wherein the compound of formula (XI) is added to a mixture of thecompound of formula (XII), the palladium catalyst and phosphine ligandsystem.
 17. A process for the preparation of a compound of formula (I-B)

comprising

reacting a compound of formula (X-B) with zinc; in the presence of asource of iodine; in a first organic solvent or a mixture of organicsolvents, wherein the first organic solvent is non-reactive to thesource iodine; to yield the corresponding compound of formula (XI-B);

reacting the compound of formula (XI-B) with a compound of formula(XII-B); in the presence of a palladium catalyst and phosphine ligandsystem; in a second organic solvent or a mixture of organic solvents; toyield the corresponding compound of formula (I-B).
 18. The process as inclaim 17, wherein the zinc is zinc powder.
 19. The process as in claim18, wherein the zinc powder is present in an amount in the range of fromabout 0.5 to about 1.5 molar equivalents.
 20. The process as in claim17, wherein the source of iodine is iodine.
 21. The process as in claim20, wherein the iodine is present in an amount in the range of fromabout 0.1 to about 0.5 molar equivalents.
 22. The process as in claim17, wherein the first organic solvent is DMAc.
 23. The process as inclaim 17, wherein the compound of formula (X-B) is reacted with the zincat a temperature of less than about 10° C.
 24. The process as in claim17, wherein the zinc and source of iodine are mixed prior to addition tothe compound of formula (X-B).
 25. The process as in claim 17, whereinthe compound of formula (XII-B) is present in an amount in the range offrom about 0.25 to about 1.0 molar equivalents.
 26. The process as inclaim 17, wherein the palladium catalyst and phosphine ligand system isa combination of Pd₂(dba)₃ and P(o-tol)₃.
 27. The process as in claim17, wherein the second organic solvent is DMAc.
 28. The process as inclaim 17, wherein the compound of formula (X-B) is reacted with thecompound of formula (XII-B) at a temperature in the range of from about50° C. to about 100° C.
 29. The process as in claim 17, wherein thecompound of formula (XI) is added to a mixture of the compound offormula (XII), the palladium catalyst and the phosphine ligand system.30. The compound prepared according to the process of claim 17.